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Since the start of the coronavirus disease (COVID-19) pandemic in 2019, many antibody therapies have been developed to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This is important because treatment reduces hospitalizations and effectively neutralizes the virus in patients with mild to moderate symptoms. Therapies developed so far mainly target the SARS-CoV-2 spike protein, but their efficiency has been reduced due to the mutation of the virus.
Research: MG1141A acts as a highly effective monoclonal neutralizing antibody against SARS-CoV-2 variants. Image source: Design_Cells/Shutterstock
In a new study published in Frontiers of Immunology, scientists have developed a universal SARS-CoV-2 neutralizing antibody MG1141A. Scientists confirmed that MG1141A retains its neutralizing activity against the alpha (UK), beta (South Africa) and gamma (Brazil) variants of SARS-CoV-2.
The spike (S) protein of SARS-CoV-2 is the main target of therapeutic agents and vaccines because it directly regulates host cell infection. The antibody neutralizes the virus by binding to the RBD of the virus S protein and preventing it from binding to the host cell receptor ACE2. However, SARS-CoV-2 variants with S protein mutations hinder this process.
The original S protein mutation is the D614G mutation in the G clade, which promotes the "upright" conformation of the RBD. All SARS-CoV-2 variants detected in 2021 have this mutation, and this mutation has not been found to reduce the efficacy of antibody therapy.
The most recent mutations, such as N501Y, K417N, E484K, and K417T, are located in the receptor binding motif (RBM), which directly binds to ACE2 in the RBD. These mutations increase the infectivity of the virus by increasing the affinity of SARS-CoV-2 to ACE2.
In addition, it must be noted that RBM is the main epitope bound by therapeutic neutralizing antibodies. Mutations in RBM will reduce the affinity of neutralizing antibodies. According to reports, these mutations also reduce the efficacy of the vaccine. Therefore, there is a need to develop therapeutic antibodies that are effective against SARS-CoV-2 variants in the future.
Scientists produced the initial candidate antibodies through mouse immunization, because human antibodies are produced in transgenic mice using human antibody genes, which provides these candidate antibodies with the potential to reduce the severity of SARS-CoV-2 variant infections. In the current study, scientists generate initial candidate antibodies by immunizing normal mice, and then humanize them to generate final antibodies. RBD whose stability is enhanced by using it in the Fc region is used as an antigen for mouse immunity.
In general, the binding affinity of antibodies tends to decrease after humanization. The KD value of MG1141A (M4 humanized clone) is maintained at 20 pM. In order to compare and analyze the efficacy of MG1141A, REGN10933 and REGN10937 from Regeneron Pharmaceuticals were used as controls.
An interesting observation is that the IC50 of MG1141A is 92 pM, which is equivalent to the neutralization effect of REGNantibodies in the neutralization test of real virus and pseudovirus. MG1141A can induce ADCC and ADCP, so it shows similar efficacy to a single monoclonal antibody in vitro. The researchers also said that MG1141A binds to different epitopes and can be used as a new type of therapeutic agent.
Human monoclonal antibodies were produced from blood from donors (N=19) during recovery from COVID-19. Scientists obtained B cell bank genes from memory B cells of donors who showed high antibody titers. A total of 99 unique antibody sequences were produced. 28 clones showing high binding were purified with IgG1 to evaluate the affinity and neutralization effect, and 5 clones that specifically bind to RBD were found. Scientists compared the efficacy of fully human monoclonal antibodies and M4 clones and confirmed that M4 has the best efficacy. Regeneron also produces antibodies from mouse immunization methods and the blood of convalescent donors.
The researchers observed that the antibody library produced by mouse immunization is better than the antibody library from humans. Convalescent donors may produce antibodies faster, which is why it is used in the early stages of COVID-19 therapy development. One limitation of this method is that after SAR-CoV-2 infection, the immune response produces antibodies at many high immunogenic sites in the S protein.
In this regard, attention must be paid to the difference between SARS-CoV-2 and RSV/Influenza. The latter can occur many times in a person's life, so many effective neutralizing antibodies can be produced.
In the case of SARS-CoV-2 designing RBD antigen to specifically bind to RBM and produce antibodies through mice, immunization is considered to be a more effective method of neutralizing antibodies than fully human antibodies from convalescent human donors .
Lee, S. etc. (2021) "MG1141A as a highly effective monoclonal neutralizing antibody against SARS-CoV-2 variants", Frontiers in Immunology, 12. doi: 10.3389/fimmu.2021.778829. https://www.frontiersin.org/articles/10.3389/fimmu.2021.778829/full
Published in: Medical News | Medical Research News | Disease/Infection News
Tags: ACE2, ADCC, antibodies, antibodies, antigens, B cells, binding affinity, blood, cells, coronavirus, coronavirus disease COVID-19, efficacy, genes, genes, immune response, immunity, immunology, in vitro, influenza, Monoclonal antibody, mutation, epidemic, drug, protein, pseudovirus, receptor, respiratory system, SARS, SARS-CoV-2, severe acute respiratory system, severe acute respiratory syndrome, spike protein, syndrome, therapeutic agent , Genetically modified, virus
Priyom has a PhD. Bachelor of Plant Biology and Biotechnology, University of Madras, India. She is an active researcher and experienced scientific writer. Priyom has also co-authored several original research articles, which have been published in well-known peer-reviewed journals. She is also an avid reader and amateur photographer.
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